Abiraterone acetate, the chemical name of which is (3β)-17-(3-pyridinyl)androsta-5,16-dien-3-yl acetate of formula 1, is the prodrug of the active metabolite Abiraterone (2), a selective inhibitor of the enzyme CYP17.

Abiraterone acetate is the active ingredient of the novel medicament Zytiga, which can be administered orally and is indicated, together with prednisone or prednisolone, for the treatment of metastatic castration-resistant prostate cancer.
Numerous processes are reported in the literature for the preparation of Abiraterone or derivatives thereof. In most cases the starting product is prasterone (dehydroepiandrosterone) or a derivative thereof of formula 3, and the key intermediate is a trifluoromethanesulphonate of formula 4 which, by Suzuki reaction with diethyl(3-pyridyl)borane or with 3-pyridylboronic acid leads, optionally after processing of the R group, to the formation of Abiraterone and/or Abiraterone acetate.

The preparation of Abiraterone acetate was originally disclosed in EP0633893 (BTG International Limited). The synthesis described in the experimental part involves the conversion of the carbonyl at the 17 position of prasterone acetate (3, R═COCH3) to the corresponding enol triflate (4, R═COCH3) by treatment with trifluoromethanesulphonic anhydride and 2,6-di-tert-butyl-4-methylpyridine. The use of said base, which among other things is rather expensive, involves the formation of an impurity deriving from the elimination of the acetate in the 3 position, which is difficult to remove without onerous chromatographic purifications. Subsequently, in WO2006/021777, BTG International Limited claimed the use of a series of bases which, as well as being more common and cheaper than 2,6-di-tert-butyl-4-methylpyridine, do not cause, or limit, the formation of said impurity.
The bases specified in the claim are pyridine, 2,6-lutidine, N-methylmorpholine, 1,4-diazabicyclo[2.2.2]octane (DABCO), trimethylamine, triethylamine, N,N-diisopropylethylamine (DIPEA), quinuclidine and 1,8-diaza-bicyclo-[5.4.0]-undec-7-ene (DBU), which are included in the more general definition of tertiary or heterocyclic amines with a pKa of the conjugate acid at 25° C. ranging between 5.12 and 12. The pKa range between 6.75 and 10.6, and in particular the use of lutidine and triethylamine, is preferred. As reported in WO2006/021777, the pKa range between 5.12 and 12, determined in aqueous solution, is critical to ensure the good result of the triflation reaction, and when bases with a comparatively low pKa of the conjugate acid (less than 5.21) are used, parallel reactions take place, with the formation of critical impurities or degradation products. This applies, for example, to 2,6-di-tert-butyl-4-methylpyridine (pKa 4.41), 2,6-di-tert-butylpyridine (pKa 4.95) and N,N-diethylaniline. For this latter base, the authors report a pKa value of the conjugate acid of 5.20, whereas higher values are reported in the literature.